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22.Ho YS, Yu MS, Yang X, et al. Neuroprotective effects of polysaccharides from Wolfberry antagonize homocysteine-induced toxicity in rat cortical neurons. J Alzheimer Dis 2010; 19: 813-827.

23.Clement CI, Goldberg I, Healey PR, Graham SL. Plasma homocysteine, MTHFR gene mutation, and open-angle glaucoma. J Glaucoma 2009; 18: 73-78.

Bilberry

Kwok-Fai So and Raymond Chuen-Chung Chang

The name bilberry, sometimes known as blueberry, whortleberry or hurts, is given to several species of low-growing shrubs in the genus Vaccinium. The one species it refers to most is Vaccinium myrtillus, which bears edible fruits. It is a potential source of natural anthocyanin antioxidants.

It has been claimed that bilberries may improve night vision, but a study on the effect of bilberry on night visual acuity and contrast sensitivity did not support this claim.1 The authors conducted a double-blind, placebo-controlled, crossover design trial using young men with good vision, comparing the effect of 160 mg of bilberry extract (25% anthocyanosides) and placebo.

In a study using streptozotocin-induced diabetic rats treated with antioxidants including troxerutin, bilberry and calcium dobesilate, the development and progression of retinopathy was followed using fundus photography.2 The VEGF-mRNA density showed an increasing tendency by 20% in the diabetic rats compared with the non-diabetic controls, and this increase was corrected by 10 mg/kg troxerutin, 50 mg/kg troxerutin and bilberry. Thus, bilberry containing high levels of anthocyanin pigments has been linked to attenuation of diabetic retinopathy.

In another study, accelerated OXYS rats with early senile cataract and macular degeneration were given control diets or diet supplemented with 25% bilberry extract (20 mg per kg of body weight including 4.5mg of antocianidin).3 At three months, > 70% of control OXYS rats exhibited cataract and macular degeneration, whereas the supplementation of bilberry extract completely prevented damage in the lenses and retinas.

References

1.Muth ER, Laurent JM, Jasper P. The effect of bilberry nutritional supplementation on night visual acuity and contrast sensitivity. Altern Med Rev 2000; 5: 164-173.

2.Chung HK, Choi SM, Ahn BO, et al. Efficacy of troxerutin on streptozotocin-induced rat model in the early stage of diabetic retinopathy. Arzneimittelforschung 2005; 55: 573-580.

3.Fursova AZH, Gesarevich OG, Gonchar AM, et al. Dietary supplementation with bilberry extract prevents macular diegeneration and cataracts in senesce-accelerated OXYS rats. Adv Gerontol 2005; 16: 76-79.

Acupuncture and glaucoma

Simon Law

Introduction

Acupuncture, a branch of Chinese traditional medicine, has been used for over 2000 years in the treatment of various illnesses. In the past two decades, it has grown in popularity in Western countries. In Chinese traditional medicine, the body is seen as a delicate balance of two opposing and inseparable forces: yin and yang. Yin represents the cold, slow, or passive principle, while yang represents the hot, excited, or active principle. An imbalance of these two forces is associated with blockage in the flow of Qi (vital force or energy) and leads to various illnesses. Qi flows along pathways known as meridians with acupuncture points on the human body that connect with them (NCCAM 2009). The underlying philosophy of acupuncture is that disorders related to the flow of Qi can be prevented or treated by stimulating the relevant acupuncture points on the body surface. The points are stimulated typically by inserting needles; however, related techniques such as manual (acupressure), electrical or laser stimulation of acupuncture points are also often included under this term.1

Mechanisms of action

The exact mechanism or physiologic process of the effects of acupuncture is far from clearly delineated. Research efforts have focused on explaining how it works within the framework of Western medicine. Different mechanisms of action have been proposed.2,3 The most commonly cited mechanism is that it stimulates the release of neurochemicals (usually endogenous opioids or serotonin). ‘Gate theory’ or segmental effects is another proposed mechanism specifically for analgesia. In the gate theory, sensory input from acupuncture is thought to block or interfere with nociceptive pain signals at the spinal level. A number of studies also report a possibility of altered physiologic functions that are regulated by the autonomic nervous system, such as heart rate, blood pressure, post-menopausal vasomotor symptoms, and respiration. By incorporating the results from studies on different systems, a model termed the broad sense hypothalamus-pituitary-adrenal (BS-HPA) axis has been proposed.2 The model hypothesizes that the central nervous system is essential for processing the effect of acupuncture by modulating the autonomic nervous system, neuroimmune system and hormonal regulation.4,5 It seems likely that different mechanisms proposed are part of an elaborate interaction of different body systems. Acupuncture may simply stimulate self-regulatory processes and this would account for reported benefits in many pathologic conditions.3

Potential effects on glaucoma

Ocular effects associated with acupuncture have been studied in animal models and small samples of subjects. Some studies report potentially beneficial effects

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of IOP reduction, improvement of central visual acuity, alteration of visual field, increase of ocular blood flow, preservation of normal waveform characteristics of multifocal electroretinogram (mfERG), alteration of visual function tested by visual evoked potential (VEP), and increase of retinal nerve growth factor.

Intraocular pressure and central vision

Most clinical studies of the effect of acupuncture on IOP and vision are case series and results are conflicting. Dabov et al.6 reported that treatment resulted in IOP reduction measured by Maklakoff tonometry in three of eight patients with glaucoma. In this study, 50 patients of a variety of eye diseases were enrolled, and all reported a subjective improvement of vision. Uhrig et al.7 reported a significant IOP decrease 15 minutes and 24 hours after acupuncture treatment in three patients with glaucoma and 15 patients with ocular hypertension. Liu et al.8 measured IOP before and five minutes after single point acupuncture in 79 eyes of 40 normal subjects. IOP was lowered in 49 eyes, increased in eight, and there was no change in 22. Mean IOP was significantly lowered by 1.61 mmHg. Wu et al.9 measured IOP after acupuncture (24.9 ± 0.9 mmHg) in 120 patients with primary open-angle glaucoma and found it significantly lower than baseline (33.7 ± 1.1 mmHg). Kurusu et al.,10 in 22 eyes of 11 patients with glaucoma, found IOP significantly reduced and visual acuity significantly improved 15 minutes after acupuncture. However, the effect weakened with time following each treatment, with subjects returning nearly to baseline levels by three to four days following a treatment. In 21 patients with POAG and 13 with OHT, Ewert and Schwanitz11 found acupuncture to lower IOP significantly. Patients also reported subjective improvement of quality of life and better compliance with medications. Wong et al.12 observed increased visual acuity but no significant change of IOP in glaucoma patients. Sold-Darseff and Leydhecker13 treated 18 patients with glaucoma and found no significant alterations of IOP.

Most, if not all, of the studies included no control group nor compared acupuncture with application of sham needles. In addition, different types of glaucoma were usually enrolled and patients were frequently on medical therapy with multiple topical drops or systemic carbonic anhydrase inhibitors.

Research conducted on animals to investigate the effects of acupuncture on IOP has been more consistent. In a rabbit model of glaucoma evaluating the effects of electroacupuncture using two acupuncture needles placed in close proximity to the sciatic nerve, Chu et al.14 noted a reduction of IOP up to nine hours after the stimulation. A simultaneous reduction of blood pressure, aqueous flow rate, and aqueous catecholamine levels (norepinephrine and dopamine) were recorded during the early time period of electroacupuncture induced hypotension, but sustained IOP reduction seems to be associated with increased aqueous humor endorphin levels. In addition, the opioid receptor antagonist, naloxone, inhibited the IOP reduction associated with electroacupuncture. The electroacupuncture-induced ocular hypotension was reduced markedly in sympathetically denervated eyes.14 IOP in dogs receiving treatment at three

acupuncture points was approximately 10% lower than in control dogs receiving no acupuncture.15 Ralston et al.16 observed a decrease in IOP following acupuncture in experimentally induced glaucoma in dogs.

Visual field

In a study to ascertain the effects of contralateral acupuncture on brain function using blind-spot mapping, 40 healthy volunteers in whom the right-side blind spot was larger than that on the left were randomly assigned a single point electroacupuncture treatment applied to a point on either the right or the left side of the body. Electroacupuncture to the contralateral side decreased the blind-spot size on perimetry, whereas that to the ipsilateral side increased the blind-spot size. The authors suggested that contralateral side electroacupuncture treatment has a better effect on brain function.17

Blood flow

Chorioretinal blood flow measured with the Heidelberg Retinal Flowmeter showed a significant increase during single point acupuncture between the thumb and forefinger in healthy young volunteers.18 Experienced subjects showed greater changes than unexperienced ones. Stimulation of specific acupuncture points produced specific effects on blood flow in arteries to the brain and eye. Blood flow velocity in the supratrochlear artery in patients with eye diseases was increased by acupuncture treatment to eye-specific acupuncture points, while no significant increase of blood flow velocity was measured in the middle cerebral artery. On the other hand, stimulation of acupuncture points believed to increase cranial circulation increased blood flow velocity in the middle cerebral artery significantly, but left the supratrochlear artery unaffected.19 In another study, blood flow velocity of the ophthalmic artery in healthy volunteers increased during acupuncture.20 Increase of blood flow volume of the central retinal artery (CRA) was associated with treatment with only one of the three acupuncture points studied along the GB meridian as measured by Color Doppler imaging and acupuncture treatment of a non-meridian acupuncture point was not associated with change of retinal blood flow.21

Multifocal ERG (mfERG)

In a rat glaucoma model, Chan et al.22 found that 2-Hz but not 100-Hz electroacupuncture treatment preserved mfERG waveform characteristics in terms of the N/P ratio. The same group had previously shown that 2-Hz electroacupuncture treatment inhibit the expression of nitric oxide synthase-2 (NOS-2), which may have a role in glaucoma damage.23

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Visual evoked potential (VEP)

Sagara et al.24 analyzed 19 healthy subjects (38 eyes) and found that in those with delayed P100 latencies of ≥ 101.7 msec (total average of the group), acupuncture stimulation contributed to a pattern reversal of the VEP by shortening the P100 latency to closer to the average.

Retinal growth factor

Applying low-frequency electroacupuncture treatment to Royal College of Surgeons (RCS) rats (an inherited retinitis pigmentosa rat model) during a critical developmental stage of retinal cell degeneration was associated with an increase of retinal nerve growth factor (NGF) protein and brain derived nerve factor (BDNF) protein and NGF high-affinity receptor (TrkA) expression, when compared with controls.25 The treatment was also associated with an increase of outer nuclear layer (ONL) thickness and enhanced vascularization.

Retinal ganglion cells (RGCs)

In rabbits subjected to high-pressure perfusion of the anterior chamber by increasing IOP to 30 mmHg and 50 mmHg, those receiving electroacupuncture treatments had more relatively intact RGC remaining compared to those without treatment.26

Limitations of study

The term acupuncture embraces a variety of stimulation techniques, including different types of acupuncture needles used, electric or laser stimulation with or without needle acupuncture, application of moxibustion with acupuncture, and acupressure without needling. In addition, different acupuncture points or groups of points, different intensity, duration, and frequency or repetition rate of stimulation were studied under the same category of acupuncture.

The acupuncture points chosen for studying the effect on glaucoma were usually based on clinical experience and traditional theory of Chinese medicine. It is important to remember that Chinese traditional medicine views diseases as an imbalance of two opposing forces, yin and yang. Therefore, the selection of points was based on the traditional way of using points for symptoms and applied to a new disease.27 Clinically, the number of main points or supplemental points to be used for treating a particular disease or symptom is not fixed and may vary during the course of acupuncture treatment based on the patient’s response. For instance, it is customary to use the traditional eye specific main points initially and judging from the response, resort to supplemental points when necessary. This clinical heterogeneity makes comparisons or analyses on studies on acupuncture difficult. For instance, the number of acupuncture points studied may vary from one to more than 20 among different studies.

Most of the studies of the effects of acupuncture on glaucoma are case series with no comparison group or control group included. A comparison group on another treatment may provide a valid differentiation of the exposure to acupuncture treatment, but possible placebo effects associated with acupuncture treatment cannot be controlled for. Some acupuncture studies on other illnesses include a control group using sham acupuncture. However, sham acupuncture may not be considered as a non-inert placebo and may elicit a physiological response. One may argue that the effects of acupuncture may not depend on specific points, location or techniques.28

Complications and safety

Relatively few complications from the use of acupuncture have been reported to the Food and Drug Administration (NCCAM 2009).

Implications

Because of ethical considerations, randomized clinical trials comparing acupuncture alone with standard glaucoma treatment or placebo are unlikely to be justified in the near future in countries where standards of care have already been established. However, trials in which acupuncture in combination with another glaucoma treatment is compared with the other glaucoma treatment alone will be of interest. It would be valuable for experienced researchers and clinicians to agree on certain basic standards in administration of acupuncture in clinical trials. Adequate data on IOP, central visual acuity, contrast sensitivity, visual field changes, optic nerve and retinal nerve fiber layer analysis, ocular blood flow, pattern electroretinography (PERG), multifocal ERG, visual evoked potential (VEP), multifocal visual evoked potential (mfVEP), potential harms, visual-related quality of life and economic outcomes will help in evaluating effectiveness and safety of acupuncture appropriately.29

References

1.Rhee DJ, Katz L, Spaeth GL, Myers JS. Complementary and alternative medicine for glaucoma. Surv Ophthalmol 2001; 46: 43-55.

2.Cho ZH, Hwang SC, Wong EK, et al. Neural substrates, experimental evidences and functional hypothesis of acupuncture mechanisms. Acta Neurol Scand 2006; 113: 370-377.

3.Moffet HH. Sham acupuncture may be as efficacious as true acupuncture: A systematic review of clinical trials. J Altern Complementary Med 2009; 15: 213-216.

4.Kim HW, Kang SY, Yoon SY, et al. Low-frequency electroacupuncture suppresses zymosaninduced peripheral inflammation via activation of sympathetic post-ganglionic neurons. Brain Res 2007; 1148: 69-75.

5.Sakai S, Hori E, Umeno K, Kitabayashi N, Ono T, Nishijo H. Specific acupuncture sensation correlates with EEGs and autonomic changes in human subjects. Auton Neurosci 2007; 133: 158-169.

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6.Dabov S, Goutoranov G, Ivanova R, Petkova N. Clinical application of acupuncture in ophthalmology. Acupunct Electrother Res 1985; 10: 79-93.

7.Uhrig S, Hummelsberger J, Brinkhaus B. [Standardized acupuncture therapy in patients with ocular hypertension or glaucoma--results of a prospective observation study]. Forsch Komplementarmed Klass Naturheilkd 2003; 10: 256-261.

8.Liu Y, Long YS, Long YS. The immediate effects of acupuncture on intraocular pressure. Chinese Acupuncture Moxibustion 1994; 14: 41.

9.Wu ZS, Yu MJ, Quan QL. The effect of acupuncture on intraocular pressure (IOP) and blood pressure (BP) of chronic glaucoma patients. Shanghai J Acupuncture Moxibustion 1998; 7: 6.

10.Kurusu M, Watanabe K, Nakazawa T, et al. Acupuncture for patients with glaucoma. Explore 2005; 1: 372-376.

11.Ewert H, Schwanitz R. [Influence of acupuncture on intraocular pressure and compliance of patients with ocular hypertension or primary wide-angle glaucoma. First results of a controlled prospective follow-up study]. Deutsche Zeitsch Akupunktur 2008; 51: 13-20.

12.Wong S, Ching R. The use of acupuncture in ophthalmology. Am J Chin Med 1980; 8: 104153.

13.Sold-Darseff J, Leydhecker W. [Acupuncture in glaucoma]. Klin Monbl Augenheilkd 1978; 173: 760-764.

14.Chu TC, Potter DE. Ocular hypotension induced by electroacupuncture. J Ocul Pharmacol Therap 2002; 18: 293-305.

15.Kim MS, Seo KM, Nam TC. Effect of acupuncture on intraocular pressure in normal dogs. J Vet Med Sci 2005; 67: 1281-1282.

16.Ralston NS. Successful treatment and management of acute glaucoma using acupuncture. Am J Acupuncture 1977; 5: 283-285.

17.Woo YM, Lee MS, Nam Y, Cho HJ, Shin BC. Effects of contralateral electroacupuncture on brain function: a double-blind, randomized, pilot clinical trial. J Altern Complement Med 2006; 12: 813-815.

18.Naruse S, Mori K, Kurihara M, et al. Chorioretinal blood flow changes following acupuncture between thumb and forefinger. Nippon Ganka Gakkai Zasshi 2000; 104: 717-723.

19.Litscher G, Wang L, Yang NH, Schwarz G. Computer-controlled acupuncture. Quantification and separation of specific effects. Neurol Res 1999; 21: 530-534.

20.Litscher G. Computer-based quantification of traditional chinese-, earand Korean hand acupuncture: needle-induced changes of regional cerebral blood flow velocity. Neurol Res 2002; 24: 377-380.

21.Mizukami M, Yano T, Yamada J. Effects of ocular circulation by acupuncture stimulation on the crus outside – the comparison of GB36, GB37, GB38, and non-meridian point. J Japan Assoc Phys Med Balneol Climatol 2006; 69: 201-212.

22.Chan HH, Leung MC, So KF. Electroacupuncture provides a new approach to neuroprotection in rats with induced glaucoma. J Altern Complementary Med 2005; 11: 315-322.

23.Leung MCP, Chan HL, Butt YKC, Ji JZ, So KF. Electro-acupuncture decreases the activity and expression of nitric oxide synthase in a rat glaucoma model. Nitric Oxide Biol Chem 2000; 4: 288.

24.Sagara Y, Fuse N, Seimiva M, et al. Visual function with acupuncture tested by visual evoked potential. Tohoku J Exp Med 2006; 209: 235-241.

25.Pagani L, Manni L, Aloe L. Effects of electroacupuncture on retinal nerve growth factor and brian-derived neurotrophic factor expression in a rat model of retinitis pigmentosa. Brain Res 2006 ; 1092: 198-206.

26.Zhou W, Yang J, Xia Y, et al. The effect of electric acupuncture on the retinal ganglion cells in rabbits with acute high intraocular pressure. In: Peng Y, Weng X (Eds.).

27.Blackwell R, Macpherson H. “Bright eyes” the treatment of eye diseases by acupuncture. J Chinese Med 1992; 39: 1-8.